In human, heterozygous mutations in DCC have been identified in families with autosomal-dominant congenital mirror movements (CMM) 14, 15, 16. However, DCC has not been detected in brainstem CST axons during normal development 8, 13, raising the possibility that DCC might influence CST midline crossing in a non cell-autonomous manner. At the level of the pyramidal decussation, the CST of Kanga mutants does not cross the midline but forms two bundles that remain in the ventral ipsilateral spinal cord 8. These mice are characterized by a striking “kangaroo-like” hopping gait, and replicate most of the commissural defects observed in Dcc −/− mutants. The study of Dcc kanga mice provided evidence supporting a role of DCC in the development of the mouse CST. Dcc kanga mice carry a spontaneous and viable Dcc mutation that removes the exon encoding the P3 intracellular domain 8. Indeed, they die within 24 hours after birth, when the CST crosses the midline and enter the spinal cord.
The role of DCC in the development of the CST has not been investigated in Dcc −/− knockout mice. DCC is considered as a cell-autonomous regulator for midline crossing, as many commissural neurons that express DCC fail to cross the midline in Dcc mutants 7, 8, 9, 12. In Dcc −/− knockout mice, midline crossing by commissural axons is altered at the level of the corpus callosum (CC), anterior commissure, hippocampal commissure 7, 8, 9, habenulo-interpeduncular system 10, inferior olive 11, and spinal cord 7, 12. DCC (Deleted in Colorectal Cancer) is a receptor that mediates the chemoattractive activity of NETRIN-1, thereby modulating the crossing of CNS commissural axons 6. To cross the midline, central nervous system (CNS) axons are guided by molecular cues whose expression, together with that of their receptors, is tightly controlled in time and space during development 4, 5. Most CST axons cross the midline at the junction between the brainstem and spinal cord, thereby forming the pyramidal decussation. The corticospinal tract (CST) is the principal motor pathway for voluntary movements 1, 2, 3. Our data unravel a new level of complexity in the role of DCC in CST guidance at the midline. Altogether, these results indicate that DCC controls CST midline crossing in both humans and mice, and that this process is non cell-autonomous in mice. Second, we show that in contrast to Kanga mice, the anatomy of the CST is not altered in mice with a deletion of DCC in the CST. First, we demonstrate by multimodal approaches, that patients with CMM due to DCC mutations have an increased proportion of ipsilateral CST projections. Here, we investigated the role of DCC in CST midline crossing both in human and mice.
As CMM has been associated, in some cases, with malformations of the pyramidal decussation, DCC might also be involved in this process in human.
Humans with heterozygous DCC mutations have congenital mirror movements (CMM). CST fails to cross the midline in Kanga mice expressing a truncated DCC protein. The corticospinal tract (CST), the principal motor pathway for voluntary movements, crosses the anatomic midline at the pyramidal decussation. DCC, a NETRIN-1 receptor, is considered as a cell-autonomous regulator for midline guidance of many commissural populations in the central nervous system.
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